Structure, three-dimensional folding, forces

The hydrophobic effect is a driving force in the formation of clathrate hydrates and the self-assembly of lipid bilayers. Hydrophobic interactions between lipids and proteins are the most important determinants of biological membrane structure. The three-dimensional folding pattern of proteins is also determined by hydrophobic interactions between nonpolar side chains of amino acid residues. 

The primary structure of a protein is its amino acid sequence. Secondary structure is the shape defined by hydrogen bonds joining the CO and NH groups of the amino acid backbone. Tertiary and quaternary structures are the three-dimensional folded arrangements of proteins that are stabilized by hydrogen bonds and other intermolecular forces. 

Although hydrogen bonds ate weak interactions, they are the single most important force determining the three-dimensional folding of proteins. The a-helix and the j0-pleated sheet, two of the proposed polypeptide hydrogen bonding schemes, have been found to be the most recurrent features that stabilize the secondary structures of proteins. 

It can be inferred from the first section of this chapter that many different forces work together in a delicate balance to determine the overall three-dimensional structure of a protein. These forces operate both within the protein structure itself and between the protein and the water solvent. How, then, does nature dictate the manner of protein folding to generate the three-dimensional... 

The three-dimensional conformation of a protein is called its tertiary structure. An a-helix can be either twisted, folded, or folded and twisted into a definite geometric pattern. These structures are stabilized by dispersion forces, hydrogen bonding, and other intermo-lecular forces. 

We encountered the properties of hydrophilic and hydrophobic molecules in our thoughts about driving forces for formation of three-dimensional protein structures. Specifically, proteins fold in a way that puts most of the hydrophobic amino acid side chains into the molecular interior, where they can enjoy each other s company and avoid the dreaded aqueous environment. At the same time, they fold to get the hydrophilic amino acid side chains onto the molecular surface, where they happily interact with that enviromnent. The same ideas are important for the double-stranded helical structure of DNA. The hydrophobic bases are localized within the double hehx, where they interact with each other, and the strongly hydrophilic sugar and phosphate groups are exposed on the exterior of the double helix to the water environment. Now, we need to understand something more about structural features that control these properties. 

Larger proteins often contain more than one polypeptide chain. These multi-subunit proteins have a more complex shape, but are still formed from the same forces that twist and fold the local polypeptide. The unique three-dimensional interaction between different polypeptides in multi-subunit proteins is called the quaternary structure. Subunits may be held together by noncovalent contacts, such as hydrophobic or ionic interactions, or by covalent disulfide bonds formed from the cysteine residue of one polypeptide chain being cross-linked to a cysteine sulfhydryl of another chain (Fig. 15). 

The overall relative orientation of the secondary structures of an enzyme determines its three-dimensional shape, or tertiary structure. Some enzymes require multiple copies of the same enzyme to function. The individual enzymes cluster into groups of two or more (called dimers, trimers, etc.) and are held together by intermolecular forces. The relative positioning of the separate enzymes in the cluster determines the overall structure, or quaternary structure, of the supramolecular complex. While all enzymes have tertiary structure, only clusters of multiple enzyme subunits have quaternary structure. The overall folded conformation of a protein in its active, catalytic form is called the active or native conformation. 

Proteins spontaneously fold into their native conformation, with the primary structure of the protein dictating its three-dimensional structure. Protein folding is driven primarily by hydrophobic forces and proceeds through an ordered set of pathways. Accessory proteins, including protein disulfide isomerases, peptidyl prolyl cis-trans isomerases, and molecular chaperones, assist proteins to fold correctly in the cell. 

Although it has been known for two decades that the three-dimensional structure of a protein is determined by its amino acid sequence, the forces that drive a disordered polypeptide chain into its final, folded conformation, and once there maintain this compact structure are only understood in general terms. There are two broad classes of noncovalent interactions... 

Nature s solution of this problem is both simple and extraordinary. The linear information of nucleotides is used to assemble a linear sequence of amino acids, and then this polypeptide chain folds on itself (because of the electrical forces that exist between amino acids) and spontaneously assumes a specific three-dimensional structure. It is as if one wrote the word apple and then observed the word folding on itself and becoming a real apple. 

Certain RNAs also possess substantial amounts of tertiary structure. Tertiary structure in RNA refers to the folding of secondary structural elements, such as double helical regions or hairpin stem-loops, into discrete three-dimensional structures. Forces involved in stabilizing such interactions are diverse, involving hydrogen-bonding, base... 

The shape adopted when two or more folded polypeptide chains aggregate into one protein complex is called the quaternary structure of the protein. Each individual polypeptide chain is called a subunit of the overall protein. Hemoglobin, for example, consists of two a and two P subunits held together by intermolecular forces in a compact three-dimensional shape. The unique function of hemoglobin is possible only when all four subunits are together. 

The formation of stable secondary structures and a unique tertiary structure of proteins are dictated by the interactions between constituent amino acid residues along the polypeptide chain and by their interactions with the surrounding medium. During the process of protein folding, the hydrophobic force drives the polypeptide chain to the folded state and overcomes the entropic factors while hydrogen bonds, ion pairs, disulhde bonds, and van der Waals interactions define the shape and keep it from falling apart. The structure of a protein mainly dictates its function, and the attainment of stable conformation is essential for proper function. Hence, many methods have been developed to determine the three-dimensional structures of proteins experimentally. 

Discussion of the field of conformational analysis and protein folding is beyond the scope of this section. Nevertheless, the concept that the most potent drugs mimic the three-dimensional ( biologically active ) structure of the native peptide bound to its receptor became an important driving force in the field of peptide chemistry. The stabilization of this structure would result in increased potency and more efficacious pharmaceuticals. 

Proteins are not just long polypeptide chains. Because of the interactions of the side chains and other forces, each protein usually folds up into a unique shape. The three-dimensional shape that the chain forms gives characteristic properties to each protein. If a polypeptide chain folds into the wrong shape, it can function differently. It may also be unable to carry out its biological role. The levels of protein structure are shown in Table 3. 

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